Medical treatment for chronic pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), commonly involves the use of bronchodilators. Bronchodilators in widespread use are β2 adrenergic receptor (adrenoceptor) agonists, such as albuterol, formoterol and salmeterol, and muscarinic receptor antagonists (anticholinergic compounds), such as ipratropium and tiotropium. These compounds are typically administered by inhalation.
It has been known in the art that, for the purpose of treating chronic pulmonary diseases, particularly COPD, administering a β2 adrenergic receptor agonist and a muscarinic receptor antagonist in combination is more effective as compared to administering each drug alone. However, since bronchodilators are used as inhalants in many cases, dosing becomes complicated or difficult when two drugs are desired to be administered and they are respectively dispensed in two inhalation devices to be administered. In addition, when two drugs are dispensed in one inhalation device, the desired formulation may differ and the chemical or physical action between the drugs may make it difficult to maintain a stable combination of the drugs.
On the other hand, compounds having both β2 adrenergic receptor agonist activity and muscarinic receptor antagonist activity produce bronchodilator effects through two distinct modes of action, although they are single molecules. Such disadvantages can be overcome by providing a drug of a single molecule having two actions. Furthermore, since such a single molecule is easier to co-formulate with another therapeutic agent to create a triple therapy combination, it would be beneficial to a patient being treated. Pharmacologically, in pulmonary tissue to which the drug is administered, the two actions are based on single molecule pharmacokinetics, so that these two actions can be synchronically exhibited. Moreover, side effects can be reduced by selecting a structural design which confers pharmacokinetic properties that cannot be achieved by combined use of two drugs or by a mixture of them. Such compounds, which are single molecules having two actions, have been reported, for example, in Patent Documents 1 to 6 and the like. However, these compounds clearly differ in structure from the compounds disclosed in the present invention.